Abstract
A large body of research has aimed to determine the neurochemical factors driving differential sensitivity to ethanol between individuals in an attempt to find predictors of ethanol abuse vulnerability. Here we find that the locomotor activating effects of ethanol are markedly greater in DBA/2J compared to C57BL/6J mice, although it is unclear as to what neurochemical differences between strains mediate this behavior. Dopamine elevations in the nucleus accumbens and caudate-putamen regulate locomotor behavior for most drugs, including ethanol; thus, we aimed to determine if differences in these regions predict strain differences in ethanol-induced locomotor activity. Previous studies suggest that ethanol interacts with the dopamine transporter, potentially mediating its locomotor activating effects; however, we found that ethanol had no effects on dopamine uptake in either strain. Ex vivo voltammetry allows for the determination of ethanol effects on presynaptic dopamine terminals, independent of drug-induced changes in firing rates of afferent inputs from either dopamine neurons or other neurotransmitter systems. However, differences in striatal dopamine dynamics did not predict the locomotor-activating effects of ethanol, since the inhibitory effects of ethanol on dopamine release were similar between strains. There were differences in presynaptic dopamine function between strains, with faster dopamine clearance in the caudate-putamen of DBA/2J mice; however, it is unclear how this difference relates to locomotor behavior. Because of the role of the dopamine system in reinforcement and reward learning, differences in dopamine signaling between the strains could have implications for addiction-related behaviors that extend beyond ethanol effects in the striatum.
Highlights
DBA/2J (DBA) and C57BL/6J (C57) mice are two inbred strains that show disparate phenotypes with respect to ethanol preference, drinking, and reward, among many other ethanolmediated behaviors [1,2,3,4,5,6]
Previous work has demonstrated that the locomotor-enhancing effects of stimulant drugs such as cocaine and amphetamine are due to their specific actions on presynaptic dopamine terminals, where they inhibit the dopamine transporter (DAT) to cause increases in synaptic dopamine levels [9,19,20]
Because DBA and C57 mice do not differ in their responses to a saline injection, their differential behavioral responses to ethanol cannot be attributed to disparate baseline locomotor activity levels
Summary
DBA/2J (DBA) and C57BL/6J (C57) mice are two inbred strains that show disparate phenotypes with respect to ethanol preference, drinking, and reward, among many other ethanolmediated behaviors [1,2,3,4,5,6]. Because DBA and C57 mice demonstrate differential responses to ethanolmediated behaviors, these strains have become valuable tools for examining the individual differences that predict ethanol abuse vulnerability. In addition to the differences in drinking behavior and ethanol reward between DBA and C57 mice, DBA mice are more sensitive to the locomotor-activating effects of ethanol [7,8], the neurochemical differences that are driving these behavioral disparities are unclear. We aimed to determine if ethanol has direct effects on dopamine terminals that could in part explain the disparities in ethanol-induced locomotion between strains
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